During normal operation of the catabolic process, energy is harvested and subsequently stored in a readily available form, namely, the phosphate bonds of adenosine triphosphate (“ATP”). When energy is required for anabolic processes, a phosphate bond of ATP is broken to yield energy for driving anabolic reactions and adenosine diphosphate (“ADP”) is regenerated. The process of catabolism involves the breakdown of proteins, polysaccharides, and lipids. Proteins are broken into smaller peptides and constituent amino acids, polysaccharides and disaccharides are broken down into their monosaccharide constituents, and lipids are broken down into glycerol and the fatty acid constituents. These compounds are further broken down into even smaller compounds, principally, two-carbon acetyl groups.
The two-carbon acetyl group, an essential component in the catabolic process, is introduced into the Krebs tricarboxylic acid cycle (“Krebs cycle”) via acetyl coenzyme A. The acetyl group serves as a carbon source for the final stages of catabolism. The Krebs cycle and an accompanying electron transport system involve a series of enzymatically controlled reactions that enable complete oxidation of the two-carbon acetyl group to form carbon dioxide and water. As shown in FIG. 1, acetyl groups are introduced into the Krebs cycle by bonding to oxaloacetic acid to form citric acid. During subsequent steps of the Krebs cycle, citric acid is converted into aconitic acid and then into isocitric acid. As isocitric acid is converted into ketoglutaric acid, one carbon atom is completely oxidized to carbon dioxide. As ketoglutaric acid is converted into succinic acid, a second carbon atom is completely oxidized to carbon dioxide. During the remaining steps, succinic acid is converted into flimaric acid, fumaric acid is converted into malic acid, and malic acid is converted into oxaloacetic acid. Each complete turn of the Krebs cycle harvests the energy of the acetyl group to yield one molecule of ATP, three molecules of nicotinamide adenine dinucleotide (“NADH”), and one molecule of flavin adenine dinucleotide FADH2. The NADH and FADH2 are subsequently used as electron donors in the electron transport system to yield additional molecules of ATP.
The Krebs cycle and the accompanying electron transport system occur in the mitochondria, which are present in different types of cells in varying numbers depending upon the cellular energy requirements. For example, neuronal and cardiac muscle cells have high numbers of mitochondria because they have extremely high energy requirements. Because of their high energy requirements, these types of cells are particularly vulnerable to disorders or conditions associated with a breakdown of the catabolic pathways or otherwise defective intracellular energy metabolism. Exemplary disorders or conditions include Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and other neurodegenerative disorders (Beal et al., “Do Defects in Mitochondrial Energy Metabolism Underlie the Pathology of Neurodegenerative Diseases?,” Trends Neurosci. 16(4):125-131 (1993); Jenkins et al., “Evidence for Impairment of Energy Metabolism in vivo in Huntington's Disease Using Localized 1H NMR Spectroscopy,” Neurol. 43:2689-2695 (1993)).
Alzheimer's Disease is one of the most common causes of disabling dementia in humans. Because Alzheimer's Disease is a progressive, degenerative illness, it affects not only the patients, but also their families and caregivers. In early stages of Alzheimer's Disease, activities of daily living are only minimally affected by cognitive or functional impairment, which may often be a first clinical sign of the disease (Small et al., “Diagnosis and Treatment of Alzheimer Disease and Related Disorders,” Consensus Statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society, JAMA 278:1363-1371 (1997)). As Alzheimer's Disease progresses, the patients' ability to perform activities of daily living diminishes and the patients become increasingly more dependent upon caregivers and other family members (see Galasko et al., “An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease,” Alzheimer Dis. Assoc. Disord. 11 (Suppl. 2):S33-S39 (1997)).
Parkinson's Disease is widely considered to be the result of degradation of the pre-synaptic dopaminergic neurons in the brain, with a subsequent decrease in the amount of the neurotransmitter dopamine that is being released. Inadequate dopamine release, therefore, leads to the onset of voluntary muscle control disturbances symptomatic of Parkinson's Disease. The motor dysfunction symptoms of Parkinson's Disease have been treated in the past using dopamine receptor agonists (including L-Dopa), monoamine oxidase binding inhibitors, tricyclic antidepressants, anticholinergics, and histamine H1-antagonists. Some investigators state that MAO inhibitors treat the primary disease process. The disease continues to progress and, frequently after a certain length of time, dopamine replacement treatment will lose its effectiveness. In addition to motor dysfunction, however, Parkinson's Disease is also characterized by neuropsychiatric disorders or symptoms. These include apathy-amotivation, depression, and dementia. Parkinson's Disease patients with dementia have been reported to respond less well to standard L-dopa therapy. Moreover, these treatments have little or no benefit with respect to the neuropsychiatric symptoms.
Huntington's Disease is a familial neurodegenerative disorder that afflicts about 1 in 10,000 individuals (Martin et al., “Huntington's Disease: Pathogenesis and Management,” N. Engl. J. Med. 315:1267-1276 (1986); Gusella, “Huntington's Disease,” Adv. Hum. Genet. 20:125-151 (1991)). Huntington's Disease is inherited in an autosomal dominant manner and is characterized by choreiform movements, dementia, and cognitive decline. The disorder usually has a mid-life onset, between the ages of 30 to 50 years, but may in some cases begin very early or much later in life. The symptoms are progressive and death typically ensues 10 to 20 years after onset, most often as the result of secondary complications of the movement disorder. The major site of pathology in Huntington's Disease is the striatum, where up to 90% of the neurons may be depleted. The impaired cognitive functions and eventual dementia may be due either to the loss of cortical neurons or to the disruption of normal activity in the cognitive portions of the basal ganglia. The characteristic chorea is believed to be caused by the neuronal loss in the striatum, although a reduction in subthalamic nucleus activity may also contribute.
Glutamate-induced neuronal cell death is believed to contribute to Huntington's Disease. Glutamate is the principal excitatory transmitter in the brain. It excites virtually all central neurons and is present in the nerve terminals in extremely high concentrations (over 10−3 M). Glutamate receptors are divided into four types (named after their model agonists): kainate receptors, N-methyl-D-aspartate (“NMDA”) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (“AMPA”) receptors, and metabolotrophic receptors. Many normal synaptic transmission events involve glutamate release. However, glutamate can also induce neurotoxicity and neuronal death at high levels (Choi, “Glutamate Neurotoxicity and Diseases of the Nervous System,” Neuron, 1:623-634 (1988)). The mechanism of cell death occurs primarily by the persistent action of glutamate on the NMDA receptors. These toxic changes produced by glutamate, called glutamate excitotoxicity, are believed to be a major cause of cell damage and death after acute brain injury such as stroke or excessive convulsions. It has been suggested that excitotoxicity may be involved in brain ischemia, Alzheimer's Disease and Huntington's Disease (Greenamyre et al., “Alterations in L-glutamate Binding in Alzheimer's and Huntington's Diseases,” Science, 227:1496-1499 (1985); Choi, “Glutamate Neurotoxicity and Diseases of the Nervous System,” Neuron, 1:623-634 (1988)).
The administration of agents that improve energy metabolism, and possibly prevent cell death, has been suggested for the treatment of disorders characterized by energy-deficient cells (Beal et al., “Do Defects in Mitochondrial Energy Metabolism Underlie the Pathology of Neurodegenerative Diseases?,” Trends Neurosci. 16(4):125-131 (1993)). One approach to augmenting the energy level of energy-deficient cells (i.e., as a result of hypoxia or hypoglycemia) involves the administration of pyruvate, which is later converted to acetate during normal metabolism. According to U.S. Pat. No. 5,395,822 to Izumi et al. (“Izumi”), the administration of pyruvate to a patient before or after an ischemic event (i.e., which produces a state of hypoxia or hypoglycemia) is sufficient to prevent neuronal degradation that normally is associated with the ischemic event. Izumi also identified the administration of glucose prior to an ischemic event as undesirable, because its administration resulted in lactic acid accumulation, which is a factor contributing to brain damage.
An approach for the treatment of Alzheimer's Disease includes the administration of NADH or nicotinamide adenine dinucleotide phosphate (“NADPH”), or the salts thereof. The administration of NADH or NADPH is described in U.S. Pat. No. 5,444,053 to Birkmayer, which discloses the use of salts formed with various acids including, among others, malic acid, succinic acid, and acetic acid. Similar approaches to treating Parkinson's Disease using NADH and NADPH are described in U.S. Pat. Nos. 5,019,561 and 4,970,200, both to Birkmayer.
U.S. Pat. No. 6,537,969 by the present inventor is directed toward overcoming these above-noted deficiencies in treating conditions associated with a breakdown of the catabolic pathways or otherwise defective intracellular energy metabolism.
Another metabolic problem is obesity. Obesity has reached epidemic proportions in the United States (Hill J O, Wyatt Hr, Reed G W, Peters J C, Obesity and the environment: where do we go from here? Science 2003; 301:598; Bray G A, Evaluation of obesity: Who are the obese?. Postgrad Med 2003; 114:19-27; Wyatt H R, The prevalence of obesity, Prim Care 2003; 30: 267-279) and in the rest of the world (Zimmerman-Belsing T, Feldt-Rasmussen U, Obesity: the new worldwide epidemic threat to general health and our complete lack of effective treatment, Endocrinology 2004; 145:1501-1502). The best available data indicate that, in 2004, over 60% of the total U.S. population is overweight or obese. The epidemic of obesity involves children and adolescents as well as adults and the elderly. All indications are that obesity is becoming more severe, not less. Obesity is recognized to be the major nutritional problem in the U.S. today and may be, or is fast becoming, the most important current public health problem in this country.
Studies of the causes of obesity and specifically of feeding behavior, including hunger and satiety, are extensive. The mechanisms involved are complex at the levels of brain anatomy, physiology, pharmacology, endocrinology, biochemistry and molecular biology. Certain relatively simple generalizations can, however, be validly made. Obesity is the result of ingesting more energy in the form of calories in food than is expended in the normal activities of the body, including exercise. (In other words, the first law of Thermodynamics holds.) If the amount of food is not limited, people eat until they are satisfied. The relationship among amount and type of food ingested, nutritional needs defined in terms of physiology, and satisfaction with eating (satiation) is very complex. It involves emotional as well as “rational” factors. For instance, change in the amount of food ingested can be a sign of depression or mania or other disorders affecting mood/affect. At a milder level, “binge eating” is a well-known response to emotional, professional and other stresses.
Amphetamine is a “weight loss” medication that has been useful in controlling excessive appetite and the resulting obesity, but that is not now used for this purpose because of its side effects (Makris A P, Rush C R, Frederich R C, Kelly T H, Wake-promoting agents with different mechanisms of action: comparison of effects of madafinil and amphetamine on food intake and cardiovascular activity, Appetite 2004; 42: 185-195; Kuo D Y, Further evidence for the mediation of both subtypes of dopamine D1/D2 receptors and cerebral neuropeptide Y (NPY) in amphetamine-induced appetite suppression, Behav Brain Res 2003; 147: 149-155). It can cause dangerous changes in the heart including cardiac death, and it can easily over-stimulate the brain. Chronic amphetamine use can cause a syndrome that resembles schizophrenia. Therefore, there is a need for an alternative approach that utilizes the effects of amphetamine in combating overweight/obesity without incurring the unacceptable side effects of amphetamine itself.
2-Phenylethylamine (β-phenylethylamine) is a normal constituent of the diet that has “amphetamine-like” affects, but is much less potent than amphetamine itself and is not dangerous (Kato M, Ishida K, Chuma T, Abe K, Shigenaga T, Taguchi K, Miyatake T, β-Phenylethylamine modulates acetylcholine release in the rat striatum: involvement of a dopamine D(2) receptor mechanism, Eur J Pharmacol 2001; 418: 65-71; Gianutsos G, Chute S, Pharmacological changes induced by repeated exposure to phenylethylamine, Pharmacol Biochem Behav 1986; 25: 129-134; Kuroki T, Tsutsumi T, Hirano M, Matsumoto T, Tatebayashi Y, Nishiyama K, Uchimura H, Shiraishi A, Nakahara T, Nakamura K, Behavioral sensitization to β-phenylethylamine (PEA): enduring modifications of specific dopaminergic neuron systems in the rat, Psychopharmacology 1990; 102: 5-10; Barroso N, Rodriguez M, Action of β-phenylethylamine and related amines on nigrostriatal dopamine neurotransmission, Eur J Pharmacol 1996; 297: 195-203). 2-Phenylethylamine (“2PE”) is a normal constituent of chocolate and of many cheeses, among other foodstuffs. 2PE is present in chocolate itself at about 60 μg/gm chocolate or more, and significantly higher in unprocessed cocoa and a number of cheeses (Baker G B, Wong J T, Coutts R T, Pasutto F. Simultaneous extraction and quantitation of several bioactive amines in cheese and chocolate, J Chromatogr 1987; 392: 317-31). A “chocolate binge” could lead to the ingestion of about 3 mg of 2PE. Experimental animals have ingested amounts of 2PE over 10,000 times higher than this for months (Kuroki T, Tsutsumi T, Hirano M, Matsumoto T, Tatebayashi Y, Nishiyama K, Uchimura H, Shiraishi A, Nakahara T, Nakamura K, Behavioral sensitization to β-phenylethylamine (PEA): enduring modifications of specific dopaminergic neuron systems in the rat, Psychopharmacology 1990; 102: 5-10). 2PE stimulates, albeit more weakly, the same dopamine (D1 and D2) receptors that amphetamine stimulates. Some of the medicinal effects of chocolate and other preparations of the cocoa bean have been attributed to 2PE, notably the satisfying and calming aspects. 2PE appears to have a mild anti-depressant affect (Paetsch P R, Greenshaw A J, 2-Phenylethylamine-induced changes in catecholamine receptor density: implications for antidepressant drug action, Neurochem Res 1993; 18: 1015-1022). 2PE levels are not consistently altered in patients with psychosis (Szymanski H V, Naylor E W, Karoum F, Plasma phenylethylamine and phenylalanine in chronic schizophrenic patients, Biol Pyschiat 1987; 22: 194-198).
One of the major problems in treating obesity is the tendency for people to regain the weight they have lost. Animal studies indicate that this effect is due at least in part to inadequate stimulation of dopamine receptors in the brain after weight loss. Pothos et al. concluded that “Low extracellular DA [dopamine] may also underlie the increase in food and drug intake typically observed in underweight animals and humans when they attempt to restore extracellular DA levels by natural or artificial means.” (Pothos E N, Creese I, Hoebel B G, Restricted eating with weight loss selectively decreases extracellular dopamine in the nucleus accumbens and alters dopamine response to amphetamine, morphine, and food intake, J Neurosci 1995; 15: 5540-6650.) These observations are in accord with extensive data on humans who regain weight after weight loss, even though available techniques do not allow direct measurement of these parameters in the brains of living humans. The drive to eat too much reflects the chemistry of the brain, not the nutritional needs of the whole body. The alteration in brain chemistry drives the harmful excess intake of calories. The obvious treatment is to feed a material that restores the physiological action in the brain that was diminished by weight loss, and does so without inducing unacceptable side effects. The action of the low extracellular DA can presumably be restored by feeding either precursors of dopamine (notably L-DOPA) or mimics of dopamine actions such as amphetamine. Though L-DOPA has been used (usually with carbidopa) to treat Parkinson's Disease, it has well known and severe side effects that limit its use even for that disease. The unacceptable side effects of amphetamine as a weight loss medication have been discussed above. Ingestion of 2PE in low mg amounts allows the mimicking of the action of extracellular DA without significant side effects.
Chocolate is now accepted to have additional beneficial health effects due to its contents of antioxidants. (The sweet science: dark chocolate may be good for you, Harv Health Lett. 2004; 29:7; Lee K W, Kim Y J, Lee H J, Lee C Y, Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine, J Agric Food Chem. 2003; 51: 7292-5.) These health effects are apart from its effects on mood and satiety, which are more reasonably attributed to its content of 2PE. Polyphenols are antioxidants that are found in both chocolate and red wine and have beneficial effects (Lee K W, Kim Y J, Lee H J, Lee C Y, Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine, J Agric Food Chem. 2003; 51: 7292-5; Constant J, Alcohol, ischemic heart disease, and the French paradox, Clin Cardiol. 1997; 20: 420-4).
The addition of a Krebs tricarboxylic acid cycle substrate (such as malate) and of a source of substrate (pyruvate derived from glucose) can be expected to enhance the antioxidant activity of the antioxidant compounds found in chocolate, since the combination of glucose and a Krebs cycle substrate can be expected to enhance the ability of the brain cells to generate the reducing equivalents needed to carry out antioxidant activities. Calculations of free radical production in normal humans indicate that it is impossible to ingest enough “antioxidant” to significantly reduce the burden of free radicals produced during normal human metabolism. The “priming” of the parts of the cells that produce the reducing equivalents necessary to regenerate antioxidants is therefore critical. Glucose and malate are particularly appropriate for producing the desired effect, since both cross easily into the brain across the “blood-brain barrier.” Use of glucose rather than another sugar has the advantage that it promptly elevates blood glucose and thereby brain glucose, increasing satisfaction and satiation and providing an “energy boost.”
In preparing a form of chocolate that contains added 2PE, as well as glucose, calcium malate, and added antioxidant as disclosed herein, it is advisable to use a vegetable oil to allow the mixing together of the ingredients. A particularly healthy form of vegetable oil is that from flax seed, due to its contents of ω-3 fatty acids (Bloedon L T, Szapary P O, Flaxseed and cardiovascular risk, Nutr Rev 2004; 62: 18-27; Prasad K, Dietary flax seed in prevention of hypercholesterolemic atherosclerosis, Atherosclerosis 1997; 132: 69-76).
Phenylethylamine (PEA), is also found in some red wines, promotes energy and elevates mood. A deficiency in PEA renders the person weak, tired, sluggish and depressed. Taking PEA rapidly restores well-being. PEA is a natural, physiological treatment of depression. Approximately 60% of depressed patients have a reduction in PEA metabolism, and PEA is effective in 60% of depressed patients. PEA relieves depression rapidly, in a matter of hours or days, and produces no toxic effects, tolerance or abuse. PEA controls depression in 60% of depressed persons—the same percentage as major antidepressants such as Prozac—but is less toxic. See Sabelli, H. (2002). Phenylethylamine deficit and replacement in depressive Illness. In D. Mishooulon and J. F. Rosenbaum. (Eds.), Natural medications for psychiatric disorders. (pp 83-110), Baltimore: Lippencott Williams and Wilkins; also see Sabelli, H. (2000). Aminoacid precusors for depression. Psychiatric Times, 17. 42-49.
Lipids are concentrated sources of energy as well as structural components of cell membranes. Everybody needs a certain amount of dietary fat for normal body functions. When fats are digested, emulsified and absorbed, they facilitate the intestinal absorption and transport of fat soluble vitamins A, D, E and K. They are also used to cushion and protect the heart, kidneys and liver. In certain climates, subcutaneous body fat helps to insulate the body from the cold and prevent heat loss through the skin. These functions can be met by a daily intake of 15 to 25 grams of fat. Lipids provide the body with maximum energy (9 kcal per gram), approximately twice that for an equal amount of protein or carbohydrates.
Lipids enter the body through the mouth and pass to the stomach, but are little affected by its acidic environment. They are absorbed primarily in the small intestines, where they are emulsified by salts of the bile acids and are hydrolyzed to fatty acids and glycerol by various water-soluble enzymes (lipases). From the intestines, the hydrolyzed lipids enter the bloodstream and are transported to other organs, mainly the liver, for further metabolism. Ultimately the fatty acids may be degraded to carbon dioxide and water to furnish energy.
There are many types of fatty acids, but they can be divided into three groups—saturated fats, monounsaturated fats and polyunsaturated fats. Polyunsaturated fats include ω-3 and ω-6 fatty acids, among others. Intake of ω-3 and ω-6 fatty acids is known to protect against atherosclerosis, which contributes to metabolic insufficiency in the brain, heart and other tissue by impairing their blood supply. A major polyunsaturated fatty acid is arachidonic acid, which is neither ω-3 nor ω-6.
There exists a need in the art for pharmaceutical compositions that provide the combined benefits of the pharmaceutical formulations of U.S. Pat. No. 6,537,969 with the benefits of phenylethylamine, antioxidants and/or unsaturated lipids (e.g., ω-3 and ω-6 fatty acids). There exists a further need in the art to improve palatability of the pharmaceutical formulations of U.S. Pat. No. 6,537,969.
All documents referred to herein are incorporated by reference in their entireties for all purposes.